Our understanding of prostate cancer has grown enormously over the past several years. From a treatment perspective, it has become clear that castration-resistant prostate cancer (CRPC) mainly owes this property to reactivation of androgen receptor (AR) signaling pathways. This has led to new targeted therapies, which have just received or are nearing FDA approval, but these have substantial shortcomings. One of these is the novel antiandrogen MDV3100 discovered and developed by our lab (Tran et al Science 2009). Roughly half of CRPC patients present with therapy-resistant disease and most of those who initially respond acquire resistance over time. We have conducted in vitro and in vivo screens of acquired resistance to MDV3100 in two human prostate cancer model systems. Transcriptome analysis of dozens of drug-sensitive and drug-resistant pairs revealed a novel, common resistance mechanism. Unlike the primary mechanism of resistance to first generation antiandrogen therapy which occurs due to upregulation of AR (Chen et al Nat Med 2004), resistance to MDV3100 is consistently associated with upregulation of the glucocorticoid receptor (GR). Furthermore, many AR target genes remain inhibited in drug-resistant tumors, indicating that the classical AR signaling pathway remains inhibited by MDV3100. However, expression of some AR target genes is restored but in a manner that is now dependent on GR. We propose a model whereby resistance to MDV3100 (and perhaps other next generation antiandrogens) occurs through nuclear receptor bypass (GR replaces AR). Here we will explore the molecular basis by which GR selectively activates certain AR target genes (Aim 1), the functional role of GR, AR and the GR/AR target gene SGK1 in maintaining drug resistance (Aim 2), and the clinical relevance of these findings in circulating tumor cells obtained from patients t treatment start and at relapse (Aim 3).